A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus

Abstract A four-site haplotype system at the dopamine D2 receptor locus (DRD2) has been studied in a global sample of 28 distinct populations. The haplotype system spans about 25 kb, encompassing the coding region of the gene. The four individual markers include three TaqI restriction site polymorphisms (RSPs) – TaqI “A”, “B”, and “D” sites – and one dinucleotide short tandem repeat polymorphism (STRP). All four of the marker systems are polymorphic in all regions of the world and in most individual populations. The haplotype system shows the highest average heterozygosity in Africa, a slightly lower average heterozygosity in Europe, and the lowest average heterozygosities in East Asia and the Americas. Across all populations, 20 of the 48 possible haplotypes reached a frequency of at least 5% in at least one population sample. However, no single population had more than six haplotypes reaching that frequency. In general, African populations had more haplotypes present in each population and more haplotypes occurring at a frequency of at least 5% in that population. Permutation tests for significance of overall disequilibrium (all sites considered simultaneously) were highly significant (P<0.001) in all 28 populations. Except for three African samples, the pairwise disequilibrium between the outermost RSP markers, TaqI “B” and “A”, was highly significant with D’ values greater than 0.8; in two of those exceptions the RSP marker was not polymorphic. Except for those same two African populations, the 16-repeat allele at the STRP also showed highly significant disequilibrium with the TaqI “B” site in all populations, with D’ values usually greater than 0.7. Only four haplotypes account for more than 70% of all chromosomes in virtually all non-African populations, and two of those haplotypes account for more than 70% of all chromosomes in most East Asian and Amerindian populations. A new measure of the amount of overall disequilibrium shows least disequilibrium in African populations, somewhat more in European populations, and the greatest amount in East Asian and Amerindian populations. This pattern seems best explained by random genetic drift with low levels of recombination, a low mutation rate at the STRP, and essentially no recurrent mutation at the RSP sites, all in conjunction with an “Out of Africa” model for recent human evolution.

[1]  S. Tishkoff,et al.  Global Patterns of Linkage Disequilibrium at the CD4 Locus and Modern Human Origins , 1996, Science.

[2]  A. Saiardi,et al.  Dopamine D2 receptors in signal transduction and behavior. , 1997, Critical reviews in neurobiology.

[3]  K. Blum,et al.  No structural mutation in the dopamine D2 receptor gene in alcoholism or schizophrenia. Analysis using denaturing gradient gel electrophoresis. , 1994, JAMA.

[4]  C. Sing,et al.  A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping. IV. Nested analyses with cladogram uncertainty and recombination. , 1993, Genetics.

[5]  M. Stoneking,et al.  mtDNA control-region sequence variation suggests multiple independent origins of an "Asian-specific" 9-bp deletion in sub-Saharan Africans. , 1996, American journal of human genetics.

[6]  N. Takahata,et al.  Allelic genealogy and human evolution. , 1993, Molecular biology and evolution.

[7]  A. Templeton.  Cladistic approaches to identifying determinants of variability in multifactorial phenotypes and the evolutionary significance of variation in the human genome. , 2007, Ciba Foundation symposium.

[8]  R. Griffiths,et al.  Archaic African and Asian lineages in the genetic ancestry of modern humans. , 1997, American journal of human genetics.

[9]  J. Crow.  Spontaneous mutation as a risk factor. , 1995, Experimental and clinical immunogenetics.

[10]  J Krushkal,et al.  Rates of nucleotide substitution in primates and rodents and the generation-time effect hypothesis. , 1996, Molecular phylogenetics and evolution.

[11]  K. Kidd,et al.  D2 dopamine receptor alleles do not influence severity of Tourette's syndrome. Results from four large kindreds. , 1994, Archives of neurology.

[12]  K. Kidd,et al.  Minisatellite diversity supports a recent African origin for modern humans , 1996, Nature Genetics.

[13]  R. Todd,et al.  A new TaqI RFLP within intron 2 of human dopamine D2 receptor gene (DRD2). , 1991, Nucleic acids research.

[14]  K. Neiswanger,et al.  Association and linkage studies of the TAQI A1 allele at the dopamine D2 receptor gene in samples of female and male alcoholics. , 1995, American journal of medical genetics.

[15]  T. Arinami,et al.  A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. , 1997, Human molecular genetics.

[16]  K. Kidd,et al.  Analyses of cross species polymerase chain reaction products to infer the ancestral state of human polymorphisms. , 1998, DNA sequence : the journal of DNA sequencing and mapping.

[17]  D. Grandy,et al.  Cloning of the cDNA and gene for a human D2 dopamine receptor. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[18]  B. Sommer,et al.  The dopamine D2 receptor: two molecular forms generated by alternative splicing. , 1989, The EMBO journal.

[19]  A J Pakstis,et al.  Evolution of haplotypes at the DRD2 locus. , 1995, American journal of human genetics.

[20]  A. Wilson,et al.  Mitochondrial DNA sequences in single hairs from a southern African population. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[21]  K. Jellinger,et al.  Schizophrenia: Normal Sequence in the Dopamine D2 Receptor Region that Couples to G-Proteins. DNA Polymorphisms in D2 , 1993, Neuropsychopharmacology.

[22]  J. Weissenbach,et al.  The CEPH consortium linkage map of human chromosome 11. , 1995, Genomics.

[23]  S. Minoshima,et al.  Structure and expression of human and rat D2 dopamine receptor genes , 1992, Neurochemistry International.

[24]  R. Lewontin.  The Interaction of Selection and Linkage. I. General Considerations; Heterotic Models. , 1964, Genetics.

[25]  C. Robert Cloninger,et al.  Linkage disequilibria at the D2 dopamine receptor locus (DRD2) in alcoholics and controls. , 1994, Genomics.

[26]  Laurent Excoffier,et al.  Testing for linkage disequilibrium in genotypic data using the Expectation-Maximization algorithm , 1996, Heredity.

[27]  M. Goodman,et al.  A molecular view of primate phylogeny and important systematic and evolutionary questions. , 1989, Molecular biology and evolution.

[28]  K. Kidd,et al.  Evolution of a D2 dopamine receptor intron within the great apes and humans. , 1998, DNA sequence : the journal of DNA sequencing and mapping.

[29]  K. Kidd,et al.  The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus , 1996, Human Genetics.

[30]  D. Grandy,et al.  Detection and characterization of additional DNA polymorphisms in the dopamine D2 receptor gene. , 1991, Genomics.

[31]  L. Cavalli-Sforza,et al.  High resolution of human evolutionary trees with polymorphic microsatellites , 1994, Nature.

[32]  K K Kidd,et al.  A global haplotype analysis of the myotonic dystrophy locus: implications for the evolution of modern humans and for the origin of myotonic dystrophy mutations. , 1998, American journal of human genetics.

[33]  K. K. Kidd,et al.  Molecular biology and human diversity: A nuclear perspective on human evolution , 1996 .

[34]  K. Kidd,et al.  HAPLO: a program using the EM algorithm to estimate the frequencies of multi-site haplotypes. , 1995, The Journal of heredity.

[35]  D. Sibley,et al.  Functional Analysis of the Human D2 Dopamine Receptor Missense Variants* , 1996, The Journal of Biological Chemistry.

[36]  W. Speed,et al.  Short tandem repeat polymorphism evolution in humans , 1998, European Journal of Human Genetics.

[37]  C. Maclean,et al.  Exclusion of linkage between schizophrenia and the D2 dopamine receptor gene region of chromosome 11q in 112 Irish multiplex families. , 1993, Archives of general psychiatry.

[38]  D. Goldman,et al.  Population and pedigree studies reveal a lack of association between the dopamine D2 receptor gene and alcoholism. , 1990, JAMA.

[39]  B. Weir.  Genetic Data Analysis II. , 1997 .

[40]  K. Kidd,et al.  Population frequencies of the A1 allele at the dopamine D2 receptor locus , 1993, Biological Psychiatry.

[41]  K. Kidd,et al.  No linkage between D2 dopamine receptor gene region and schizophrenia. , 1991, Archives of general psychiatry.

[42]  C. Sing,et al.  A cladistic analysis of phenotype associations with haplotypes inferred from restriction endonuclease mapping. II. The analysis of natural populations. , 1988, Genetics.

[43]  G. Uhl,et al.  Dopamine D2 receptor RFLPs, haplotypes and their association with substance use in black and Caucasian research volunteers. , 1993, Human heredity.

[44]  K. Kidd,et al.  DRD2 haplotypes containing the TaqI A1 allele: implications for alcoholism research. , 1996, Alcoholism, clinical and experimental research.

[45]  D. Rubin,et al.  Maximum likelihood from incomplete data via the EM - algorithm plus discussions on the paper , 1977 .

[46]  L. Jin,et al.  Population genetics of dinucleotide (dC-dA)n.(dG-dT)n polymorphisms in world populations. , 1995, American journal of human genetics.

[47]  D. F. Roberts,et al.  The History and Geography of Human Genes , 1996 .

[48]  A. Spurdle,et al.  Y chromosome probe p49a detects complex PvuII haplotypes and many new TaqI haplotypes in southern African populations. , 1992, American journal of human genetics.

[49]  D. Grandy,et al.  The human dopamine D2 receptor gene is located on chromosome 11 at q22-q23 and identifies a TaqI RFLP. , 1989, American journal of human genetics.

[50]  K. Kidd,et al.  Gilles de la Tourette syndrome is not linked to D2-dopamine receptor. , 1990, Archives of general psychiatry.

[51]  M. Itokawa,et al.  A structural polymorphism of human dopamine D2 receptor, D2(Ser311-->Cys). , 1993, Biochemical and biophysical research communications.

[52]  P. Seeman,et al.  Dopamine receptor pharmacology. , 1994, Trends in pharmacological sciences.

[53]  D. Grandy,et al.  Direct sequencing of the dopamine D2 receptor (DRD2) in schizophrenics reveals three polymorphisms but no structural change in the receptor. , 1991, Genomics.

[54]  J. Long,et al.  Linkage and association of a functional DRD2 variant [Ser311Cys] and DRD2 markers to alcoholism, substance abuse and schizophrenia in Southwestern American Indians. , 1997, American journal of medical genetics.